linkage mapping, whole-exome sequencing; a homozygous NMNAT1 mutation was found in the original, consanguineous, LCA9 Pakistani family and additional mutations found in many other LCA families; common findings include early-onset optic atrophy and neonatal degeneration of the central retina (colobomas); the NMNAT1 protein is a nuclear isoform of the rate-limiting enzyme in NAD+ synthesis and may serve a neuroprotective role

candidate gene; dominant mutation in a large Turkish family; affected family members have early-onset optic atrophy and adult-onset neuropathy; dominant-acting MFN2 mutations are a common cause of CMT and hereditary motor and sensory neuropathy; MFN2 protein is involved in fusion of mitochondria and contributes to mitochondrial morphology and distribution

homozygosity mapping, whole-exome sequencing; rare, novel homozygous missense mutation in a multiplex Saudi RP family and the same homozygous mutation in an isolated Saudi RP patient; protein is a component of the endoplasmic reticulum with unknown function

homozygosity mapping, whole-exome sequencing; homozygous mutation identified in a consanguineous family of South Asian origin; biallelic mutations found in additional families; symptoms include benign yellow-white retinal lesions or flecks with otherwise normal retinal findings; the PLA2G5 protein is a secretary phospholipase which plays a role in phagocytosis of photoreceptor outer segment discs by RPE cells

homozygosity mapping, whole-exome sequencing; homozygous Lys42Glu mutation in an American family and 15 Israeli families of Ashkenazi Jewish origin; may account for 10% of recessive RP in Israel; the DHDDS gene is widely expressed, including in rod and cone photoreceptors; the protein is an enzyme in the dolichol synthesis pathway and dolichol is involved in biosynthesis of N-linked oligosaccharide chains on proteins such as rhodopsin; this mutation causes RP only but mutations in other genes affecting oligosaccharide synthesis cause multi-system disorders

candidate gene; accounts for 2% of recessive RP and 6 to 16% of LCA; same as RPE65-/- Swedish Briard-Beagle dog; protein is necessary for production of 11-cis-vitamin A; 9-cis-retinal restores visual function in mouse model; successful gene therapy in dog; in same pathway as LRAT; dominant mutation in large Irish family with several members diagnosed with choroideremia

homozygosity mapping, whole-exome sequencing; homozygous or compound heterozygous mutations found in five unrelated Pakistani, Indian and European families with adult-onset retinal dystrophy and early macular involvement; the DRAM2 gene product is a widely-expressed, transmembrane protein which initiates autophagy, that is, degradation of cells and cellular components, and may play a role in photoreceptor disc recycling

homozygosity mapping, whole-exome sequencing; homozygous and compound heterozygous mutations in ATF6 have been identified in more than ten families with achromatopsia, including a consanguineous Pakistani family and an isolated case, suggesting this is a common cause of disease; achromatopsia is a congenital or early-onset cone dysfunction disorder; symptoms include color blindness, photophobia, nystagmus and reduced visual acuity; the ATF6 protein is a transmembrane transcription factor, involved in the unfolded protein response, which localizes throughout the neural retina and RPE

linkage mapping, candidate gene; a Gln5345Arg mutation that segregates with disease in one family is the probable cause of ARMD1; possible association with AMD but CFH is the more likely reason for association; fibulins are extracellular matrix proteins with multiple EGF domains, others include EFEMP1 and FBLN5

linkage mapping, association study; a common histidine allele at a polymorphic Tyr402His site in control module 7 of CFH increases the life-time risk of AMD 2-to-7 fold; extended haplotypes including other complement genes also contribute; CFH and/or the haplotypes probably account for the AMD linkage peak at this location; rare recessive mutations in CFH cause nephropathy and hemolytic-uremic syndrome; mutations in trans to the His 402 variant cause early-onset drusen; AMD is also associated with complement genes C2, CFB and C3

animal model, candidate gene; homozygous mutations in one LCA family; rd3 mouse has a recessive mutation in this gene which causes retinal degeneration with intact photoreceptors at birth but otherwise early onset and rapid progression; protein of unknown function

whole-genome sequencing; a homozygous frameshift mutation detected in a Japanese RP patient and the same mutation (heterozygous) in a second patient; the NEK2 gene product is a widely-expressed ciliary-associated protein involved in cell division and implicated in several cancers; NEK2 is expressed in retina and inactivation in zebrafish results in photoreceptor defects

linkage mapping, sequencing; linkage mapping in a Dutch-German family and a Japanese family; PCARP is a rare, childhood-onset neurodegenerative syndrome involving spinal cord degeneration and RP; FLVR1 expression is most abundant in retina and secondarily in spinal cord and brain; function of the FLVCR1 protein is unknown but may involve heme/iron homeostasis

linkage mapping, candidate gene; usherin is a basement membrane protein, with laminin EGF and fibronectin type III domains, found in many tissues including capillary and structural basement membranes in retina and inner ear; causes 30 to 40% of USH type 2 and 10 to 15% of recessive RP; common ancestral c.2299delG mutation of European origin with atypical phenotype; Cys759Phe mutation found in 4 to 5% of recessive RP without hearing loss; an additional 51 exons have been identified; common c.4338delCT founder mutation in French Canadians and Acadians as is another in USH1C

homozygosity mapping, whole-exome sequencing; 12 distinct mutations in 10 families; nephronophthisis-related ciliopathies involve dysplasia or degeneration of kidney, retina and/or cerebellum; BBS cases have early renal disease but not polydactyly; SDCCAG8 protein, first identified as a colon cancer antigen, localizes to centrioles and interacts with other ciliopathy-associated proteins including OFD1, and plays a broad role in kidney, retina and brain development

whole exome sequencing; a single-missense mutation identified in two independent Chinese families by exome sequencing; the OR2W3 gene product is in the olfactory receptor family but olfactory receptors have functions in addition to olfaction and ORF2 is expressed in multiple tissues including thyroid and RPE cells; the OR2W3 transcript overlaps with TRIM58, a larger gene of unknown function

Chromosome 2

linkage mapping, candidate gene; mapping in a consanguineous Pakistani family; zinc finger genes are a large family of expression factors, many with unknown specificity; ZNF513 is expressed in the retina, including photoreceptors; knockdown in zebrafish affects eye morphology and leads to loss of photoreceptors suggesting a role in retinal development and maintenance

whole-exome sequencing; clinical consequences of mutations in IFT172 range from non-syndromic RP to Bardet-Biedl syndrome to complex skeletal, renal, hepatic, retinal and cerebellar syndromes (also called Jeune and Mainzer-Saladino syndromes); variable clinical phenotypes do not clearly correspond to different mutation types; the IFT172 protein is involved in intraflagellar transport and plays a role similar to other proteins involved in complex, highly variable ciliopathies

homozygosity mapping, candidate gene; Dutch, Israeli and other consanguineous families; C2orf71 is an open reading frame within a gene coding for a novel protein with no known homology; the gene is highly expressed in retina, primarily in photoreceptors, and the protein localizes to primary cilia; morpholino knockdown in zebrafish produces visual defects; the C2orfF71 gene is highly variable complicating mutation screening; mutations in this gene cause progressive retinal atrophy, rcd4, in Gordon Setter and Irish Setter dogs; a mutation in C2orf71 may modify Usher syndrome caused by CEP250

linkage mapping, candidate gene; Arg345Trp mutation found in all affected individuals to date; normal protein is secreted from RPE but mutant protein is misfolded and retained in RPE; both proteins accumulate between the RPE and drusen, but not within drusen; possible model for age- related macular degeneration; fibulins are extracellular matrix proteins with multiple EGF domains, others include FBNL5 and FBLN6; knock-in mouse shows AMD phenotype

recessive retinitis pigmentosa; protein: family with sequence similarity 161 member A
[Gene]

homozygosity mapping, candidate gene; consanguineous Indian family, and Israeli and German families; FAM161A codes for a protein of unknown function expressed in retina, brain and testis, but largely localized to photoreceptors

candidate gene; homozygous mutation in one BBS family; heterozygous variants may act as modifiers of BBS and Meckel-Gruber syndrome; protein plays a role in planar cell polarity during embryogenesis and may affect ciliogenesis

homozygosity mapping, candidate gene; total color blindness and other cone-related abnormalities (rod monochromacy); CNGA3 accounts for 20-30% of achromatopsia cases whereas CNGB3 accounts for uo to 50% and GNAT2 accounts for a minor fraction; most common cause of achromatopsia and CORD in Chinese

linkage mapping, candidate gene; Chinese families (one is the family in which RP33 was mapped), in addition to several European families; also known as activating signal cointegrator I complex subunit 3-like 1, the gene is widely expressed and codes for a splice-complex protein as do several other dominant RP genes

linkage mapping, candidate gene; also called Jalili syndrome, with cone-rod dystrophy and amelogenesis imperfecta (abnormal tooth enamel and development); more than 7 independently-ascertained families including a consanguineous Arab family and a Kosovo family; cyclin M4 protein is involved in metal ion transport, with expression in neural retina and developing teeth suggesting a connection between tooth biomineralization and retinal function

linkage mapping, candidate gene; mutations found in several families with BBS mapped to 2q31; the BBS5 protein, identified by proteomics analysis of flagellar proteins, is a highly-conserved component of flagella and cilia, and may interact with BBS1; may account for 2% of BBS cases

linkage mapping, candidate gene; two Spanish families with the same homozygous mutation and families with other mutations; ceramide kinases are involved in neuronal cell survival and apoptosis; CERKL is expressed in retinal ganglion cells among other tissues; CERKL mutations cause widespread retinal degeneration with maculopathy; a founder splice-site mutation in CERKL accounts for 33% of recessive retinal degeneration cases among Yemenite Jews

homozygosity mapping, whole-exome sequencing; homozygous mutation in Canadian Hutterite families with Joubert syndrome and other mutations in additional families; symptoms of Joubert syndrome include RP, polydactyly and brain abnormalities; the TMEM237 protein localizes to the ciliary transition zone (TZ) in multiple tissues, including photoreceptors, is a component of a complex interaction network in the TZ, and plays a role in ciliogenesis, gastrulation and Wnt signaling

linkage mapping, candidate gene; dominant vitreoretinal disease in an American family of European origin with developmental and progressive abnormalities affecting multiple tissues of the eye including early-onset cataracts, retinal deposits and retinal detachment; recessive LCA in two consanguineous families without other ocular abnormalities; protein is a member of the Kir family (Kir7.1) of inwardly-rectifying potassium channels often involved in maintaining resting membrane potential

linkage mapping, candidate gene; mapped in Dutch, Chinese and American families; retinal vasculopathy and cerebral leukodystrophy are progressive and have onset in middle age; TREX1 protein is a major 3'-5' DNA exonuclease that performs a proofreading function; symptoms of related disorders include microangiopathy, aneurysms and telangiectasia of retinal capillaries, often accompanied by numbness and cold sensitivity in fingers (Raynaud phenomenon), and CNS degeneration

homozygosity and linkage mapping, candidate gene; Bedouin, Saudi, American and Canadian families; mild phenotype with normal IQ, reversible obesity and polydactyly of the feet only in many patients; BBS proteins, probably including ARL6, play roles in ciliary function, and homologous sequences are found in ciliated microorganisms; four siblings in a consanguineous Saudi Arabian family are homozygous for an ARL6 missense mutation but have RP only and no BBS findings

homozygosity mapping, candidate gene; mapping in a Dutch family and an Iraqi Jewish family with additional mutations in several populations; generally early onset RP but macuopathy in one case; protein is a component of the retinal intercellular matrix

linkage mapping, candidate gene; clarin-1 is a novel, 4-transmembrane protein with a possible role in hair cell and photoreceptor synapses; accounts for 40% of Usher syndrome in Finland; possible digenic deafness with MYO7A; recessive RP with no hearing loss in two consanguineous Pakistani families

whole-exome sequencing; a homozygous SLC7A14 missense mutation detected in a Chinese RP family and additional missense mutations found in other Chinese families; mutations in SLC7A14 account for 2% of autosomal recessive RP in these patients; SLC7A14 is expressed in retina and the central nervous system; the gene product is a potential cationic transporter protein with an unknown ligand; zebrafish downregulation and a knockout mouse show a similar phenotype

linkage mapping, candidate gene; gene is widely expressed and abundant in retina; protein is a dynamin-related GTPase which localizes to mitochondria; OPA1 mutations cause 30 to 50% of dominant optic atrophy; disease may be a consequence of haploinsufficiency with reduced penetrance; a Utah OPA1 family has optic atrophy, sensorioneural hearing loss, ptosis and ophthalmoplegia, and polymorphic OPA1 alleles may be associated with normal tension glaucoma

linkage mapping, candidate gene; same as retinal degeneration in the rd1 mouse, rd10 mouse and rcd1 Irish Setter dog; accounts for 3 to 4% of recessive RP; photoreceptor rescue with calcium-channel blocker in mouse but not dog

homozygosity mapping, candidate gene; oculoauricular syndrome involves developmental abnormalities of the outer ear, ocular anterior segment and retina leading to retinal degeneration and loss of vision at an early age; two families, a Swiss family with a homozygous HMX1 deletion and a consanguineous Pakistani family with a homozygous missense mutation, have been reported; the HMX1 gene product plays an unknown role in embryogenesis

homozygosity mapping, whole-exome sequencing; German and Moroccan-Jewish families; symptoms include progressive cone-rod dystrophy, loss of visual function, hyperpigmentation of the macula and RPE atrophy, starting in childhood or teens; RAB28 proteins localize to the photoreceptor basal body and may be involved in ciliary transport

homozygosity mapping, candidate gene; homozygous mutation in CC2D2A in a consanguineous Pakistani family with 5 retarded individuals, all with accompanying RP; the CC2D2A protein is widely expressed and may play a role in calcium-dependent signal transduction; Joubert syndrome, also known as cerebello-oculo-renal syndrome, involves highly variable cerebellar and cognitive abnormalities, cystic kidney disease (nephronophthisis), and retinitis pigmentosa or Leber congenital amaurosis; related diseases caused by recessive CC2D2A mutations include COACH syndrome and Meckel syndrome

whole-exome sequencing; in addition to retinal anomalies (RP), recessive mutations in WDR19 cause a wide range of diseases and symptoms including asphyxiating thoracic dysplasia (Jeune syndrome), cranioectodermal dysplasia (Sensenbrenner syndrome) and nephronophthisis; the WDR19 protein is a member of the intraflagellar transport A complex involved in ciliary function

whole-exome sequencing; distinct compound heterozygous mutations in two isolated cases; function of the gene product is unknown but the protein localizes to the outer plexiform layer of the retina in a pattern similar to other CSNB proteins

homozygosity mapping; mapping in Gypsy families and mutations in other families; the BBS12 gene is 1 mb from the BBS7 gene which was excluded by sequencing; protein has sequence similarity to other BBS genes and is a member of the type II chaperonin superfamily with possible ciliary function

candidate gene, association study; based on the possible role of TLR4 in AMD, association was tested to a TLR3 Leu412Phe polymorphism (rs3775291) in AMD patients with geographic atrophy; the Phe allele was protective in the original and replicate samples; subsequent studies failed to confirm this finding; toll-like receptors recognize microorganisms and then initiate an immune response

linkage mapping, candidate gene; symptoms include RP and glistening crystals in the retina, cornea and lymphocytes; more common in Asians; gene is a member of the cytochrome P450 superfamily, homologous to mouse CYP4V3; protein may play a role in fatty acid and steroid metabolism; one mutation, c.802-8_810del17insGC, accounts for 65% of alleles in Chinese patients; compound heterozygous mutations in CYP4V2 reported in a Chinese family with RP but no other findings of crystalline corneoretinal dystrophy

linkage mapping, candidate gene; intronic mutations in several families including the original Wagner family; disease may be a consequence of an imbalance in the ratio of normal splice variants; vitreoretinopathy alone (Brown 95) or with ocular abnormalities (Black 99a) are allelic; versican is a component of extracellular matrix in the vitreous and binds to hyaluronan and link protein to form aggregates which maintain structural integrity

linkage mapping, candidate gene; five unrelated families with mild RP and possible dental abnormalities but without seizures; protein is a very large cell-surface calcium-binding G protein-coupled receptor; same gene as in recessive Frings mouse with seizures from sudden noise, and humans with febrile seizures; originally believed limited to females, but in males too; USH2B family later assigned to GRP98

homozygosity mapping, whole-exome sequencing; homozygous Tyr454Ser mutations in a Mennonite (Plain) family in Pennsylvania and in an unrelated Old Order Amish family in Canada; the Tyr454Ser variant has an allele frequency of 1.5% in Old Order Amish; disease symptoms are consistent with Usher syndrome III but also include motor development delay, truncal ataxia and gait abnormalities; some affected children have infection-induced hallucinations (Charles Bonnet syndrome) and rare sudden death; the HARS protein is an enzyme which catalyzes the synthesis of histidyl-transfer RNA (his-tRNA); his-tRNA, in turn, is necessary for incorporation of histidine into proteins

Chromosome 6

whole-exome sequencing; exome sequencing identified a homozygous Alu insertion in 21 independently-ascertained probands with recessive RP, all of Jewish ancestry; exome sequencing and cis-regulatory mapping identified nonsense and missense mutations in Turkish and Dutch RP families; MAK is expressed in multiple tissues including spermatogonia and retina; the protein is a kinase involved in regulation of retinal cilium and spermatogenesis

association study; C2 and CFB are contiguous genes within 500 bp of each other with multiple variants in high linkage disequilibrium; certain C2-CFB haplotypes significantly increase the risk of AMD and others are protective; both proteins have roles in innate immunity and inflammation; deficiency of C2 is associated with autoimmune disease; AMD is also associated with complement genes C3 and CHF

linkage mapping, candidate gene; two Dominican families and others; protein localizes to developing and adult rods and cones; possibly involved in transport of rhodopsin from inner to outer segment; a similar gene in tub mouse causes obesity, deafness and retinal degeneration; the TULP1gene shares homology with the TUB gene associated with recessive retinal dystrophy and obesity

homozygosity mapping, linkage mapping, candidate gene; Spanish and Pakistani families; accounts for 10 to 20% of recessive RP in Spain and 12% in France, and is a common cause of RP in China; the EYS gene, one of the largest human genes (2.0 mb), codes for a 3,165 AA extracellular matrix protein; EYS is a composite of EGFL11 and Drosophila eys proteins and contains at least 21 EGF and 5 LamG domains; mutations in Drosophila eys cause structural abnormalities in rhabdomeres; gene missing or non-functional in some mammals, including mouse

linkage mapping; North Carolina, German, Belizean and British families; MCDR1 is clinically distinct from PBCRA (same locus) but similar to MCDR3 (different locus); current linkage interval is 3 cM (1.8 mb); no potential MCDR1 mutation found in IMPG1

linkage mapping, candidate gene, whole-exome sequencing; an identical dominant missense mutation found in three European families and homozygous and compound heterozygous mutations found in two recessive families; an IMPG1 mutation may also account for dominant benign concentric annular macular dytrophy (BCAMD); the IMPG1 protein is a component of the photoreceptor extracellular matrix; mutations in other extracellular matrix proteins also cause vitelliform macular dystrophy, suggesting a common disease mechanism

homozygosity mapping, linkage mapping; Pakistani, American Old Order River Brethren, and European families with homozygous mutations in lebercilin, including the original LCA5 family; the LCA5 gene is widely expressed and abundant in retina; lebercilin localizes to photoreceptor connecting cilia, and other cilia and microtubules, and interacts with numerous ciliary proteins including OFD1; although LCA5 mutations might, theoretically, cause complex ciliopathies, null mutations affect the retina only

linkage mapping, candidate gene; six independent families; accounts for 1 to 2% of autosomal dominant RP cases; the locus is outside of the RP9 linkage region; KLHL7 is a member of the BTB-Kelch superfamily (containing a series of Drosophila protein motifs) and plays a role in the ubiquitin-proteasome pathway leading to protein degradation

linkage mapping, candidate gene; mutations in PAP1 may cause the RP9 form of RP but there is doubt - the original His137Leu "mutation" may be a paralogous variant (concurrent sequence from a gene and a pseudogene) and no additional mutations have been reported to segregate with disease; PAP1 is a widely-expressed gene; protein has a role in pre-mRNA splicing and interacts with a U2-complex splice factor

homozygosity mapping, candidate gene; several small, consanguineous families; identified by a combination of mapping, comparative genomic analysis and gene expression studies; expression is down regulated by PTH but function of protein is unknown

candidate gene; Refsum disease is a peroxisomal disorder of branched-chain lipid metabolism, with progressive RP, peripheral neuropathy, cerebellar ataxia and additional findings; also known as Zellweger syndrome, phytanic acid storage disease and other disorders; see also PEX7, PHYH and PXMP3

linkage mapping, candidate gene; Spanish, Scottish and American families; IMPDH1 is one of two widely-expressed isoforms in humans; IMPDH's are highly-conserved enzymes, found in bacteria and eukaryotes, which catalyzes the rate-limiting step in de novo guanine synthesis; a common IMPDH1 mutation, Asp226Asn, is at a site conserved in all species and accounts for at least 2% of all dominant RP; mutations affect polynucleotide binding (e.g., to rhodopsin mRNA) by the CBS domains but not enzyme activity

linkage mapping, candidate gene; mapping and sequencing candidate genes in Japanese families with occult macular dystrophy (OMD) revealed a missense mutation in three families and a second mutation in a fourth family; OMD involves central cone dysfunction and loss of vision with a normal-appearing retina; other RP1L1 variants are associated with a wide range of symptoms including retinitis pigmentosa alone; RP1L1 and RP1 proteins are 35% identical and interact with photoreceptor connecting cilia; the RP1L1 gene is highly variable complicating mutation screening

linkage mapping, candidate gene; four consanguineous families including the original Brazilian CORD9 family; early onset in humans with loss of peripheral and central vision; widely expressed gene; homozygous knockout mouse has mild retinopathy and no other overt symptoms; ADAM9 protein is involved in cell-matrix interactions and acts as an adhesion molecule binding integrins; OMD involves central cone dysfunction and loss of vision with a normal-appearing retina; RP1L1 and RP1 proteins are 35% identical and interact with photoreceptor connecting cilia

whole-exome sequencing; recessive mutations in HGSNAT were first identified in patients with type IIIC mucopolysaccharidosis, also called Sanfilippo syndrome C, with symptoms of severe central nervous system degeneration and retinal dystrophy; recessive mutations were found subsequently in patients with RP but without neurologic disease or other symptoms; the HGSNAT protein, also called N-acetyltransferase, acetylates heparin and heparan sulfate in lysosomes and is abundant in retina; Sanfilippo syndrome is a classic lysosomal storage disease affecting neurologic tissues

linkage mapping, candidate gene; causes 5 to 10% of adRP; large Kentucky family and others; highly variable expression; two common mutations, Arg677X and 2280del4; protein is photoreceptor-specific, with similarity to doublecortin, and localizes to connecting cilia; homozygous insertions and deletions in Pakistani families; mutations in a similar gene, RP1L1, also cause retinal disease; common recessive Ser542X founder mutation in Spanish patients

candidate gene; Refsum disease is a peroxisomal disorder of branched-chain lipid metabolism, with progressive RP, peripheral neuropathy, cerebellar ataxia and additional findings; also known as Zellweger syndrome, phytanic acid storage disease and other disorders; see also PEX1, PEX7 and PHYH

linkage mapping, candidate gene; symptoms include total color blindness, photophobia and nystagmus; European and American families, and 4-10% of Pingelapese on the Eastern Caroline Islands; protein generates cone electrical response; common 1148delC mutation; CNGB3 accounts for up 50% of achromatopsia cases whereas CNGA3 accounts for 20-30% and GNAT2 accounts for a minor fraction; same as cd in Alaskan Malamute and German Pointer dogs; ACHM1 family reassigned to CNGB3

homozygosity mapping, whole-exome sequencing; homozygous mutation in an Israeli family and additional homozygous mutations in other families, original mutation has an allele frequency of greater than 1% in Israelis of Druze origin; the C8otf37 protein, of unknown function, localizes to the base of cilia in retinal photoreceptors and RPE cells

homozygosity mapping, candidate gene; mutations in several unrelated families; symptoms include progressive visual loss with supernormal ERG response to a bright flash of light - suggesting an abnormal potassium current in photoreceptor inner segments; protein (also called Kv11.1) is expressed in rods and cones and must coassemble with other subunits to form an active voltage-gated potassium channel

linkage mapping, candidate gene; RP31 mapped in a French Canadian family, TOPORS mutations also found in European families; early symptoms include a perivascular cuff of RPE atrophy surrounding the superior and inferior retinal arcades, later progressing to diffuse pigmentary retinopathy; TOPORS protein is widely expressed and localizes to the basal body of connecting cilia in photoreceptors; morpholino silencing in zebrafish affects retinal development

linkage mapping, whole-exome sequencing; a heterozygous nucleotide substitution found in a five-generation British family with dominant retinal degeneration and bilateral iris coloboma (holes); miR-204 is a small micro RNA which plays a role in vertebrate eye development and photoreceptor maintenance; the mutation affects miRNA-204 targeting, and knockouts in a medaka fish model replicate findings in humans

targeted-capture next-generation sequencing; a heterozygous PRPF4 missense mutation and a regulatory deletion were identified in a dominant RP family and an isolated case, respectively; the PRPF4 protein is a member of the U4/U6-U5 splice complex which includes several other proteins causing dominant RP; a functional null mutation in PRPF4 suggests haploinsufficiency as a disease mechanism

linkage mapping, association study; linkage mapping indicated an AMD locus at this site and a polymorphic Asp299Gly amino acid substitution in TLR4 showed association with life-time risk of AMD in Caucasians; a subsequent study did not replicate this finding; toll-like receptors recognize microorganisms and then initiate an immune response; TLR4 produces a widely-expressed transmembrane protein which recognizes lipopolysaccharide from Gram-negative bacteria; the Gly allele is protective against atherosclerosis; see also TLR3

linkage mapping; genome-wide linkage mapping in a consanguineous Pakistani family with type 1 Usher syndrome localized the disease locus to chromosome 10 with a two-point lod score of 3.8; the locus overlaps with PCDH15 (USH1F) but sequencing uncovered no mutations; also overlaps with DFNB33

linkage mapping, whole-exome sequencing; a missense mutation, Glu847Lys, was identified in a large Louisiana family with dominant RP and in four other unrelated dominant RP families from Louisiana, Canada and Sicily; one family member homozygous for the mutation has severe, early-onset RP; heterozygotes are more mildly affected; the mutation tracks with an uncommon haplotype of 450 kb suggesting an ancient founder event; hexokinase 1 catalyzes phosphorylation of glucose to glucose-6-phosphate; recessive null mutations are associated with hemolytic anemia and neuropathy, symptoms not observed in the RP families

homozygosity mapping, candidate gene; homozygous mutations in four families, two with cone dystrophy and two with achromatopsia (absent cones and/or color vision); several additional heterozygous mutations in other patients; PDE6C protein is a component of cone cGMP phosphodiesterase which plays a central role in cone phototransduction

chromosomal translocation; homozygous chromosomal translocation breakpoint in the PDZK7 gene in an 8 year old child with hearing loss but no retinal disease; included as a likely Usher syndrome gene (not in Summaries); gene interacts with DFNB31 and USH1C proteins; may modify other Usher mutations

association study, candidate gene; a SNP (rs10490924), within LOC387715 in a region on 10q linked to AMD, has the second highest association with AMD of neighboring SNPs, but whether LOC387715 is a functioning gene is disputed; the SNP encodes a possible serine risk allele (Ala69Ser); an LOC387715 transcript is found in many tissues including retina; the predicted gene product is a hypothetical protein of unknown function; the LOC387715-HTRA1 associated SNPs are 6 kb apart

association study, candidate gene; a SNP (rs11200638), which is 512 bp 5' of HTRA1 in a region on10q linked to AMD, has the highest association with AMD of neighboring SNPS; the risk allele may enhance expression; the HTRA protein is a serine protease that degrades insulin-like growth factors; the protein is present in AMD drusen and may regulate degradation of extracellular matrix; the HTRA1-LOC387715 associated SNPs are 6 kb apart

linkage mapping, whole-exome sequencing; missense and frame-shift mutations in ZNF408 were first identified in Dutch families with dominant familial exudative vitreoretinopathy (FEVR); symptoms of FEVR include retinal neovascularization, vitreous exudates and hemorrhage, and retinal detachment; subsequently, homozygous mutations were identified in a Spanish family and an isolated case with RP and vitreal abnormalities but without FEVR; the ZNF408 protein is a zinc-finger transcription factor involved in retinal development and maintenance

linkage mapping, candidate gene; also known as Sveinsson peripapillary chorioretinal degeneration, helicoid, with symmetrical lesions radiating from the optic disc; large Icelandic family; protein enhances transcription in the retina and other tissues

linkage mapping, candidate gene; accounts for approximately 40% of BBS families; a ubiquitously-expressed gene of unknown function but with weak similarity to BBS2; a common Met390Arg mutation can cause classic Bardet-Biedl symptoms in some patients and non-syndromic retinitis pigmentosa alone in others; evidence does not support triallelic inheritance with BBS2, BBS4 or MKKS

animal model, candidate gene, homozygosity mapping; recessive CSNB mutations in two families and LCA in a third consanguineous Bedouin family; expression of CABP4 is limited to retina; protein localizes to photoreceptor synaptic terminals and may modulate voltage-dependent calcium channels; Cabp4-null mice have a phenotype similar to CSNB; mutations in patients reduce transcript levels to 30 to 40% of normal; the CSNB diagnosis is disputed

linkage mapping, candidate gene; mutations found in three families; dominant neoovascular inflammatory vitreoretinopathy is an autoimmune disorder with progressive symptoms similar to uveitis, RP and diabetic retinopathy; disease locus (VRNI) was originally mapped in 1992; calpains are calcium-dependent cysteine proteases involved in signal transduction; CAPN5 is expressed in photoreceptors

linkage mapping, candidate gene; MY07A is an unconventional myosin, a component of cilia and microvilli, found in several tissues including inner ear hair cells, photoreceptors and RPE; same gene affected in sh1 shaker-1 mouse (but no RP) and mariner zebrafish; possible digenic deafness with USH3A; MYO7A functions as an actin-based motor protein involved in opsin transport in photoreceptors, RPE phagocytosis, and transport and localization of melanosomes in RPE cells

homozygosity mapping, sequencing; Arg55ter mutation in a large inbred Algerian family and other families from the region; transmembrane mitochondrial protein of unknown function, consistent with role of mitochondria in optic neuropathy

linkage mapping, candidate gene; common mutation (Ser163Arg) found in 7 of 14 families with late-onset retinal degeneration (L-ORD), a possible model for AMD; C1QTNF5 protein is a small collagen secreted by RPE, a possible constituent of Bruch's membrane; another missense mutation is associated with a complex ocular phenotype including lens zonules

animal model, candidate gene; one affected homozygous sibship; protein is a subunit of a voltage-gated L-type calcium channel complex in photoreceptor ribbon synapses; first identified in a spontaneous, homozygous mouse model with retinopathy similar to CSNB; gene is widely expressed

candidate gene; a homozygous Ser12X mutation in PDE6H from a common ancestor was found in Dutch and Belgium families; an earlier report of a heterozygous mutation in patients with cone dystrophy was not supported by subsequent studies; PDE6H protein is expressed in all cone photoreceptors although patients have preserved short-wavelength cone function

linkage mapping; a maximum LOD score of 4.1 in one US family of Russian origin; affected individuals have optic nerve head anomalies including optic pits, coloboma and "morning glory" anomaly, with serous macular detachments and macular disease, but normal intraocular pressures

linkage and homozygosity mapping, whole-exome sequencing; a homozygous Arg106Pro mutation was identified in consanguineous Turkish and Iraqi families with non-syndromic cone or cone-rod dystrophy, or with Leber congenital amaurosis, Joubert syndrome and polycystic kidney disease, respectively; different compound heterozygous mutations found in an additional patient with CORD; the POC1B protein localizes to the primary cilium in photoreceptors and knockdown in zebrafish results in abnormal ocular development and retinal degeneration

whole-exome sequencing; a missense mutation identified segregating in a large family with inner retinal dysfunction and ganglion cell abnormalities but normal cerebral functioning; protein elongation mutations found in families with dominant dementia and cerebral amyloid angiopathy; protein of unknown function which localizes to retinal inner nuclear and ganglion cell layers

candidate gene; mutations in 4 to 6% of patients; RPGRIP1 protein interacts with RPGR, with species-specific colocalization (rod and cone outer segments in humans, connecting cilia in mice); high sequence similarity to RPGRIP1L; suggestion of same gene in the cord1 longhaired dachshund dog but later discounted

candidate gene; de novo mutation in a boy with early onset retinal dystrophy and pituitary dysfunction including failure to thrive, poor feeding and growth hormone deficiency; recessive mutations in OTX2 cause microphthalmia and cerebral abnormalities; OTX2 protein is a member of the bicoid family of homeodomain transcription factors expressed in brain and involved in retinal and ocular development

whole-exome sequencing; compound heterozygous frame-shift mutations identified in an Italian-American family with recessive RP and facial dysmorphology, developmental delay, and short stature; the RDH11 protein is a widely-expressed enzyme with a role in oxidizing 11-cis-retinol to 11-cis-retinal in the visual cycle, a role similar to RDH5 and RDH12

homozygosity mapping, candidate gene, linkage mapping; French families and consanguineous Austrian families; symptoms include severe progressive rod-cone dystrophy and macular atrophy; may account for 4% of recessive LCA; protein is involved in visual cycle and has unusual dual specificity for all-trans-retinols and cis-retinols; same pathway as RDH5 and RDH11; also a large North Carolina family with a dominant mutation

whole-exome sequencing; homozygous and compound heterozygous mutations found in four unrelated families, primarily of European origin, with "cone first" retinal dystrophy; the TTLL5 gene product is a tubulin glutamylase implicated in polyglutamylation of primary photoreceptor cilia and sperm flagellar function, thus this is an additional retinal ciliopathy

homozygosity mapping, sequencing; Saudi Arabian, Dutch and other families including original LCA3 family; the SPATA7 protein is found in spermatocytes and multiple retinal layers; not a ciliary protein

candidate gene; TTC8 protein includes a prokaryotic domain, pilF, involved in pilus formation, localizes to ciliated structures such as the connecting cilium in photoreceptors, and interacts with PCM1, a protein involved in ciliogenesis; thus BBS proteins play a role in basal body - ciliary function; multiple BBS8 families, one with random left-right body axis symmetry; non-syndromic recessive RP in a consanguineous Pakistani family

whole exome sequencing; compound heterozygous mutations found in three families with microcephaly, chorioretinopathy and other variable ocular findings including "punched out" retinal lesions; the families share a synonymous variant which induces exon skipping; the TUBGCP4 protein is involved in microtubule nucleation and organization, and contributes to brain and eye development

linkage; linkage mapping in two Pakistani families (one later shown to have CIB2 mutations) with a maximum two-point LOD score of 5.7, and linkage in a Dutch family with Usher syndrome and congenital cataract

linkage mapping, candidate gene; homozygous mutations in a large multi-generation Pakistani family; the SLC24A1 gene is expressed in multiple retinal tissues by postnatal day 7 in mice; the gene product is a member of the solute carrier protein family and may affect intracellular calcium levels in retina; an earlier survey failed to find mutations in patients with retinitis pigmentosa

homozygosity and linkage mapping, candidate gene; approximately 3 to 6% of BBS families; protein similar to O-linked N-acetylglucosamine transferases involved in signal transduction in plants and animals; involved in triallelic inheritance: two BBS2 alleles and a third BBS1, BBS4 or MKKS allele

linkage mapping, candidate gene; a homozygous CIB2 mutation was found in a Pakistani family with Usher syndrome, originally called USH1H, but subsequently shown to be outside this region and hence called "USH1J"; other CIB2 mutations found in several Pakistani families with nonsyndromic deafness; CIB2 protein localizes to stereocilia of inner ear hair cells, photoreceptors and RPE; protein is a component of the Usher interactome

whole-exome sequencing; exome sequencing identified a homozygous deletion in a consanguineous Canadian family with RP and spondyloepiphyseal dysplasia; other mutations in GNPTG cause mucolipidosis with skeletal and joint abnormalities but no reported retinal findings; GNPTG protein is involved in post-translational modification and trafficking of lysosomal hydrolyses

linkage mapping, candidate gene; symptoms include progressive abnormalities in skin, retinal Bruch membrane and arteries leading to hemorrhage, calcification and vascular changes, with retinal angioid streaks; may be an extracellular transport protein; ABCC6 mutations in 60 to 80% of patients

homozygosity mapping, candidate gene; several families with Joubert syndrome; clinical findings include cystic kidney disease (nephronophthisis), cerebellar and cognitive abnormalities, and rare retinal dystrophy; one of a growing class of ciliopathy-associated genes affecting photoreceptors; RPGRIP1L has high sequence similarity to RPGRIP1; the protein interacts with NPHP4 protein and other ciliary proteins and is a modifier of other retinal ciliopathies

linkage mapping, candidate gene; BBS2 mutations found in a large Bedouin family and approximately 20% of BBS families; protein of unknown function with sequence similarity to BBS7; missense mutations in BBS2 may also cause non-syndromic retinitis pigmentosa alone; triallelic inheritance may be required for Bardet-Biedl syndrome, that is, two BBS2 alleles and a third BBS1, BBS4 or MKKS allele

homozygosity mapping, whole-exome sequencing; unrelated homozygous mutations detected in two consanguineous families, Arab-Muslim and European, respectively; affected individuals have RP and variable additional findings consistent with cilia-associated diseases; the ARL2BP protein is widely-expressed, localizes to photoreceptor connecting cilia and may play a role in trafficking of ciliary proteins and factors

homozygosity mapping, candidate gene; consanguineous French family; CNGB1 encodes a complex transcription unit with at least 6 non-overlapping transcripts, one of which is the disease gene in this case

linkage mapping; mapped in a large Italian family with a maximum lod score of 8.8; optic atrophy in the family is frequently associated with late-onset sensorineural hearing loss, increased central conductance times and cardiac abnormalities accompanied by increased mitochondrial biogenesis

homozygosity mapping, candidate gene; homozygosity mapping in a consanguineous Pakistani family with recessive RP and macular coloboma (holes) led to detection of a homozygous missense mutation in DHX38; additional mutations have not been reported; the DHX38 gene product is a putative RNA helicase involved in pre-RNA splicing

homozygosity mapping, whole-exome sequencing; Knobloch syndrome is a developmental disorder of the eye and occipital region of the skull, with symptoms including myopia, cataract, dislocated lens, vitreoretinal degeneration and retinal detachment; a homozygous missense mutation was identified in ADAMTS18 in an Italian patient with early-onset retinal dystrophy and autism disorder but no additional eye findings; the protein is expressed in adult photoreceptors and knockdown in medaka fish produces a phenotype similar to the human disease

linkage mapping, mutation screening; a CORD family was mapped to this region and incorrectly called "CORD5", but was later found to have a GUCY2D mutation; the original CORD5 family has a mutation in PITPNM3

linkage mapping, candidate gene; South African and European families; highly-conserved, ubiquitously-expressed member of the U4/U6-U5 tri-snRNP particle complex including PRPF3 (RP18), PRPF6 and PRP31 (RP11)

linkage mapping, candidate gene; CORD5 was originally mapped in a Swedish family, one of two later found to have a missense mutation in PITPNM3; protein is involved in phospholipid transport and photoreceptor membrane renewal; mutations in the homologous Drosophila gene cause retinal degeneration B (rdgB)

linkage mapping, candidate gene; North African and other families; causes 10 to 20% of recessive LCA and up to 40% of dominant COD or CORD; same gene affected in rd/rd chicken; lentiviral expression of GUCY2D restores vision in this model; most mutations causing COD or CORD are found in codon 838 (arginine) and arise on different haplotypes

animal model, whole-exome sequencing; mutations in several independently-ascertained families; homozygous GPR179 mutation in the nob5 mouse; GPR179 is a G protein-coupled receptor expressed in retinal bipolar cells; CSNB patients have reduced or absent b-wave response as a result of bipolar cell abnormalities, consistent with the function of GRP179 protein

candidate gene; a pair of recessive MKS1 mutations in a Turkish BBS patient and heterozygous variants in patients with mutations in other BBS genes suggest that MKS1 mutations can be a primary cause of BBS, may cause digenic disease, and may modify clinical expression; Meckel syndrome is a severe congenital disease including brain malformations, kidney and liver disease, and polydactyly; MKS1 protein is a component of the flagellar basal body

linkage mapping, candidate gene; mutations in CA4 may cause the RP17 form of RP but there is doubt - the original Arg14Trp "mutation" is found in 4% of Swedish controls and no additional mutations have been reported to segregate with disease; same chromosomal site as dog prcd progressive rod-cone degeneration; carbonic anhydrases are Zn-containing enzymes that catalyze hydration of carbon dioxide; CA4 protein is a membrane-anchored enzyme found in pulmonary capillaries, proximal renal tubules and retinal choriocapillaris

candidate gene; homozygous mutations in several unrelated patients with slow cone adaptation to sudden light changes (bradyopsia); rods in knockout mice show slowed flash recovery; protein forms a heterotrimeric complex with R9AP and is a photoreceptor-specific member of a family of proteins that deactivate transducins

animal model, candidate gene; a single homozygous missense change accounts for recessive prcd in many dog breeds; the same mutation, Cys2Tyr (TGC→TAC), is found in a Bangladesh individual with recessive RP; the PRCD transcript is expressed throughout the retina and at much lower levels in other tissues; protein of unknown function; additional consanguineous Israeli Arab family

candidate gene; mutations in FSCN2 may cause RP and/or MD but there is doubt - the 208delG "mutation" is a benign polymorphism in Asians (in heterozygotes) and no additional, pathogenic mutations have reported; the FSCN2 protein is a photoreceptor-specific paralog of fascin which crosslinks and bundles f-actin

association study; the Arg80Gly polymorphism in C3 (rs22230199, also called Arg102Gly) is associated with AMD in English and Scottish populations; homozygotes for the glycine allele have a 2-to-3 fold increase in life-time risk; the arginine and glycine alleles produce the "slow" and "fast" C3 alleles, respectively; the Gly allele has a 17% frequency in Caucasians but is rare or absent from Africans and Asians; AMD is also associated with complement genes C2, CFB and CHF

candidate gene; RAX2 protein is a modulator of photoreceptor gene expression, present in human and bovine genomes but not, apparently, in the mouse genome; three different, heterozygous, mutations found in two isolated CORD patients and one AMD patient; mode of inheritance unknown

candidate gene; homozygous mutations in several unrelated patients with slow cone adaptation to sudden light changes (bradyopsia); protein binds to and is a regulator of RGS9, a photoreceptor-specific member of a family of proteins that deactivate transducins

linkage mapping, candidate gene; incomplete penetrance and bimodal severity result from variable expression of alleles in trans; large deletions in PRPF31, not detectable by sequencing, account for 2.5% of dominant RP; highly-conserved, ubiquitously-expressed member of the U4/U6-U5 tri-snRNP particle complex including PRPF3 (RP18), PRPF6 and PRPF8 (RP13); an intronic SNP in CONT3 contributes to incomplete expression

expression mapping; unique identification based on reduced mRNA expression in lymphoblasts; two families with low or absent expression; isocitrate dehydrogenase catalyzes conversion of isocitrate to α-ketogluterate in the citric acid cycle (Krebs cycle); the Krebs cycle is localized to mitochondria, further confirming the role of mitochondria in retinal diseases; no additional symptoms were observed in the RP patients

homozygosity mapping, candidate gene; symptoms are highly variable including progressive rigidity, pigmentary retinopathy, iron deposits in the palladium, and neurological disorders; PANK2 mutations account for at least 66% of affected families, with deletions in 4%; the PANK2 gene is ubiquitously expressed and the protein is an essential enzyme in CoA biosynthesis, catalyzing phosphorylation of pantothenate; Hallervorden's name is no longer associate with this syndrome because of his role in eugenics

linkage mapping, candidate gene; MKKS mutations also cause McKusick-Kaufman syndrome with multiple congenital and developmental anomalies in Old Order Amish families; protein has sequence similarity to chaperonins; often involved in triallelic inheritance: two BBS2 alleles and a third BBS1, BBS4 or MKKS allele

whole-exome sequencing; a homozygous nonsense mutation detected in two families with recessive rod cone dystrophy, one family of North African Sephardic Jewish origin and the other of Spanish ancestry, and compound heterozygous mutations in a third family; KIZ mutations may account for up to 1% of recessive RP patients in this population; the KIZ gene is widely expressed and its product localizes to and stabilizes centrosomes, thus this is an additional ciliopathy

homozygosity mapping, whole-exome sequencing; a homozygous nonsense mutation in CEP250 accompanied by a heterozygous or homozygous nonsense mutation in C2orf71 causes atypical Usher syndrome in a consanguineous Iranian Jewish family; the C2orf71 mutation increases severity in an additive fashion; CEP250 mutations alone may or may not be sufficient to cause Usher syndrome; the CEP250 gene product is a member of a family of proteins involved in centrosomal activity

homozygosity mapping, candidate gene; homozygosity mapping identified a homozygous missense mutation in IFT27 in a consanguineous Saudi family with two affected siblings; no additional mutations have been reported; a zebrafish model has complex ciliopathy features; the authors conclude that the IFT27 mutation is the cause of disease in this family and assign the symbol "BBS19" to this locus; the IFT27 gene product is associated with intraflagellar transport in green algae

linkage mapping, whole-exome sequencing; homozygous mutations in TUBGCP6, first observed in an Old Order Amish family, cause complex developmental disorders including microcephalic dwarfism and chorioretinal degeneration; the TUBGCP6 protein plays a key role in centriolar function and is phosphorylated by PLK4, mutations in which cause a similar phenotype

linkage mapping, candidate gene; a frameshift mutation causes Jobert syndrome in a Malaysian family with unaffected carrier females but severely affected males; symptoms include RP, polydactyly, brain and facial abnormalities, development delay and breathing problems; targeted genomic next-generation sequencing also uncovered a deep intronic mutation in a family with severe X-linked RP (the RP23 locus); OFD1 is a centrosomal protein which interacts with other ciliopathy-associated proteins including lebercilin (LCA5) and SDCCAG8

linkage mapping, candidate gene; nyctalopin is an extracellular glycosylphosphatidyl (GPI)-anchored member of the small leucine-rich proteoglycan (SLRP) protein family; expressed in several tissues but more abundant in retina and kidney; NYX mutations are found in a majority of X-linked complete-CSNB patients; NYX mutation found in the original CSNB4 family ('CSNB4' also refers to rhodopsin)

linkage mapping, candidate gene; human cofactor C is involved in beta-tubulin folding; accounts for 10% of XlRP in European and North American families; affected "carrier" females in at least one family; novel protein similar to human cofactor C

linkage mapping, candidate gene; founder mutation in Mennonites; CACNA1F mutations are found in 60 to 90% of X-linked incomplete-CSNB patients; retina-specific expression with synaptic localization of protein; mutations in AIED-like patients and later found in the original Åland Island family; associated with optic atrophy in a Japanese family; the CORDX3 locus in a Finish family later identified as a CACNA1F mutation

candidate gene; one to five copies 3' to red pigment gene or more complex organization; absence of both OPNL1LW and OPNMW, either as a result of mutations in the genes or mutations in the locus control element, cause blue-cone monochromacy (blue cones only), also called cone dystrophy 5

candidate gene; Ala180Ser polymorphism with spectral shift; absence of both OPNL1LW and OPNMW, either as a result of mutations in the genes or mutations in the locus control element, cause blue-cone monochromacy (blue cones only), also called cone dystrophy 5

sequencing; three mutations (MTND1-3460, MTND4-11778 and MTND6-14484) account for 95% of European cases and one (11778) for 80% of Japanese cases; penetrance influenced by mtDNA haplotype; uncertain role of rare variants; spontaneous recovery possible